The proton pump inhibitors are for example compounds of the general formula I ##STR1## wherein Het.sub.1 is ##STR2## Het.sub.2 is ##STR3## X= ##STR4## wherein N in the benzimidazole moiety means that one of the carbon atoms substituted by R.sub.6 -R.sub.9 optionally may be exchanged for a nitrogen atom without any substituents;
R.sub.1, R.sub.2 and R.sub.3 are the same or different and selected from hydrogen, alkyl, alkoxy optionally substituted by fluorine, alkylthio, alkoxyalkoxy, dialkylamino, piperidino, morpholino, halogen, phenyl and phenylalkoxy, PA1 R.sub.4 and R.sub.5 are the same or different and selected from hydrogen, alkyl and aralkyl; PA1 R'.sub.6 is hydrogen, halogen, trifluoromethyl, alkyl and alkoxy, PA1 R.sub.6 -R.sub.9 are the same or different and selected from hydrogen, alkyl alkoxy, halogen, halo-alkoxy, alkylcarbonyl, alkoxycarbonyl, oxazolyl trifluoroalkyl, or adjacent groups R.sub.6 -R.sub.9 form ring structures which may be further substituted; PA1 R.sub.10 is hydrogen or forms an alkylene chain together with R.sub.3 and PA1 R.sub.11 and R.sub.12 are the same or different and selected from hydrogen, halogen or alkyl or, alkoxy groups. In the above definitions, alkyl groups, alkoxy groups, and moieties thereof may be branched and straight C.sub.1 -C.sub.9 -chains or comprise cyclic alkyl groups, for example cycloalkylalkyl.
Examples of proton pump inhibitors according to formula I are ##STR5##
The proton pump inhibitors used in the dosage forms of the invention may be used in neutral form or in the form of an alkaline salt, such as for instance the Mg.sup.2+, Ca.sup.2+, Na.sup.+, K.sup.+ or Li.sup.+ salts, preferably the Mg.sup.2+ salts. Further where applicable, the compounds listed above may be used in racemic form or in the form of a substantially pure enantiomer thereof, or alkaline salts of the racemates or the single enantiomers.
Suitable proton pump inhibitors are for example disclosed in EP-A1-0005129, EP-A1-174 726, EP-A1-166 287, GB 2 163 747 and WO90/06925, WO91/19711, WO91/19712, and further especially suitable compounds are described in WO94/27988 and WO95/01977.
These proton pump inhibitors are, as already mentioned, useful for inhibiting gastric acid secretion in mammals and man. In a more general sense, they may be used for prevention and treatment of gastric-acid related diseases in mammals and man, including e.g. reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. Furthermore, they may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e.g. in patients on NSAID therapy, in patients with Non Ulcer Dyspepsia, in patients with symptomatic gastro-esophageal reflux disease, and in patients with gastrinomas. They may also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre- and postoperatively to prevent aspiration of gastric acid and to prevent and treat stress ulceration. Further, they may be useful in the treatment of Helicobacter infections and diseases related to these.
These proton pump inhibitors are, however, susceptible to degradation/transformation in acidic reacting and neutral media The degradation is catalyzed by acidic reacting compounds and the proton pump inhibitors are usually stabilized in mixtures with alkaline reacting compounds.
In respect to the stability properties of the proton pump inhibitors mentioned above, it is obvious that a proton pump inhibitor in an oral solid dosage form must be protected from contact with the acidic reacting gastric juice and the active substance must be transferred in intact form to that part of the gastrointestinal tract where pH is less acidic, neutral or alkaline and where rapid absorption of the pharmaceutically active substance, i.e. the proton pump inhibitor, can occur.
A pharmaceutical dosage form of these proton pump inhibitors is best protected from contact with acidic gastric juice by an enteric coating layer. In U.S. Pat. No. 4,853,230 such enteric coated preparations of different acid labile substances are described. Said preparations contain an alkaline core material comprising the active substance, a separating layer and an enteric coating layer.
Ordinary enteric coating layers, however, comprise compounds which contain acidic groups. If covered with such an enteric coating layer, the acid labile substance may rapidly decompose by direct or indirect contact with the acidic groups resulting in discoloration of the content and loss in content of the active compound with the passage of time. The discoloration can be avoided by applying some type of separating layer between the core material comprising the susceptible proton pump inhibitor and the enteric coating layer.
Thus, there are a lot of patent applications describing such a separating layer between a core material comprising the pharmaceutically active substance and an enteric coating layer. See for instance, U.S. Pat. No. 4,786,505, EP 0,277,741 and EP 0,342,522. The prior art techniques to apply at least two different layers on a pellet core or a tablet comprising an acid labile compound is rather complicated and there is a demand for finding new processes and formulations to simplify the manufacturing of such enteric coated articles comprising acid labile substances.